Evidence that enviroxime targets multiple components of the rhinovirus 14 replication complex

Brown‐Augsburger, Patricia; Vance, L M; Malcolm, Stuart; Hsiung, Hann-Chang; Smith, Daniel P.; Heinz, Beverly A.

doi:10.1007/s007050050611

Cited by 24 publications

(18 citation statements)

References 27 publications

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“…6d, e). This mutation has been observed previously in a PV mutant resistant to enviroxime, which inhibits the initiation of positive-strand RNA synthesis of rhinoviruses and enteroviruses, although a direct interaction of enviroxime with the 3A protein has yet to be detected (Brown-Augsburger et al, 1999;Heinz & Vance, 1995;Wikel et al, 1980). A compound called TTP-8307, which has a property similar to that of enviroxime in terms of the resistance determinant in resistant mutants, was recently described (De Palma et al, 2009 the passage of PV in the presence of GW5074 and Flt3 inhibitor II, we did not observe marked CPE in infected cells, in contrast to those in the selection with GuaHCl ( Fig.…”

Section: Discussionsupporting

confidence: 52%

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Arita

Wakita

Shimizu

2009

Journal of General Virology

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Previously, we identified a cellular kinase inhibitor, GW5074, that inhibits poliovirus (PV) and enterovirus 71 replication strongly, although its target has remained unknown. To identify the target of GW5074, we searched for cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. With this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with the identified kinase inhibitors did not affect PV replication significantly, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor suppressed the replication synthetically. The effect of AG1478 in this synthetic inhibition was compensated by other receptor tyrosine kinase inhibitors (IGF-1R inhibitor II and Flt3 inhibitor II). We isolated mutants resistant to Flt3 inhibitor II and GW5074 and found that these mutants had crossresistance to each treatment. These mutants had a common mutation in viral protein 3A that results in an amino acid change at position 70 (Ala to Thr), a mutation that was previously identified in mutants resistant to a potent anti-enterovirus compound, enviroxime. These results suggest that cellular kinase inhibitors and enviroxime have a conserved target in viral protein 3A to suppress enterovirus replication. INTRODUCTIONThe genus Enterovirus consists of at least ten species of non-enveloped viruses with a single-stranded, positivesense genomic RNA that belong to the family Picornaviridae. Enterovirus infection is mostly asymptomatic, but sometimes causes severe neurological symptoms exemplified by poliomyelitis. In infection by poliovirus (PV), which is the causative agent of poliomyelitis and belongs to the species Human enterovirus C, motor neurons are the major target for neurovirulence (Bodian, 1949). Enterovirus 71 (EV71), another neurotropic enterovirus belonging to the species Human enterovirus A, is a causative agent of hand, foot and mouth disease and herpangina, but sometimes causes severe neurological diseases, such as brainstem encephalitis and poliomyelitis-like paralysis (Chumakov et al., 1979;McMinn, 2002;Wang et al., 2003). EV71 causes fatal pulmonary oedema and pulmonary haemorrhage in young children by destruction of the vasomotor and respiratory centres in the brainstem Ho et al., 1999;Huang et al., 1999;Komatsu et al., 1999;Lum et al., 1998;Wang et al., 1999). For PV, live-attenuated and inactivated vaccines have been established and are currently being used for global eradication of poliomyelitis (Sabin, 1965;Salk et al., 1954). However, there is no effective therapeutic means for vaccine-associated...

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Section: Discussionsupporting

confidence: 52%

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Arita

Wakita

Shimizu

2009

Journal of General Virology

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“…Enviroxime-resistant enteroviruses were subsequently isolated in an attempt to identify the target of the compound. Enviroxime-resistant PV, HRV, and CVB3 were all found to carry mutations in 3A, but the resistance mechanism has remained elusive [7,8,10]. Remarkably, PV mutants that are resistant to GW5074, a kinase inhibitor that inhibits PV RNA replication, were found to contain the same amino acid alteration as mutants resistant to enviroxime [11].…”

Section: Introductionmentioning

confidence: 99%

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

et al. 2012

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RNA viruses can rapidly mutate and acquire resistance to drugs that directly target viral enzymes, which poses serious problems in a clinical context. Therefore, there is a growing interest in the development of antiviral drugs that target host factors critical for viral replication, since they are unlikely to mutate in response to therapy. We recently demonstrated that phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) and its product phosphatidylinositol-4-phosphate (PI4P) are essential for replication of enteroviruses, a group of medically important RNA viruses including poliovirus (PV), coxsackievirus, rhinovirus, and enterovirus 71. Here, we show that enviroxime and GW5074 decreased PI4P levels at the Golgi complex by directly inhibiting PI4KIIIβ. Coxsackievirus mutants resistant to these inhibitors harbor single point mutations in the non-structural protein 3A. These 3A mutations did not confer compound-resistance by restoring the activity of PI4KIIIβ in the presence of the compounds. Instead, replication of the mutant viruses no longer depended on PI4KIIIβ, since their replication was insensitive to siRNA-mediated depletion of PI4KIIIβ. The mutant viruses also did not rely on other isoforms of PI4K. Consistently, no high level of PI4P could be detected at the replication sites induced by the mutant viruses in the presence of the compounds. Collectively, these findings indicate that through specific single point mutations in 3A, CVB3 can bypass an essential host factor and lipid for its propagation, which is a new example of RNA viruses acquiring resistance against antiviral compounds, even when they directly target host factors.

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“…Enviroxime, which inhibits positive-strand RNA synthesis by preventing normal formation of the replication complex (21,26), was recently identified as a nonspecific PI4KB inhibitor, as well as PIK93 (20,22,23). Direct interaction of enviroxime with viral protein 3A or 3AB was not detected (27); however, the inhibitory effect was antagonized by a resistant mutation in the 3A-encoding region (G5318A [3A-Ala70Thr] mutation) (26).…”

mentioning

confidence: 99%

Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds

Arita

Kojima

Nagano

et al. 2013

J Virol

100

121

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Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (

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Evidence that enviroxime targets multiple components of the rhinovirus 14 replication complex

Cited by 24 publications

References 27 publications

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds

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